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Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer need to be referred to medical centers that have multidisciplinary teams of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for more information.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials under the auspices of cooperative groups such as the Children's Oncology Group (COG), the Children's Cancer and Leukaemia Group (CCLG), and the Société Internationale d'Oncologie Pédiatrique (SIOP). Information about ongoing clinical trials is available from the NCI Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2006, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Childhood kidney cancers account for about 7% of all childhood cancers. Most childhood kidney cancers are Wilms tumor, but in the 15- to 19-year age group, most tumors are renal cell carcinoma. Wilms tumor can affect one kidney (unilateral) or both kidneys (bilateral). Other types of childhood kidney tumors include rhabdoid tumors, clear cell sarcoma, congenital mesoblastic nephroma, neuroepithelial tumors, desmoplastic small round cell tumor, cystic partially differentiated nephroblastoma, multilocular cystic nephroma, primary renal synovial sarcoma, and anaplastic sarcoma. Nephroblastomatosis of the kidney is a type of nonmalignant neoplasia.[3,4]
The incidence of Wilms tumor is 7.1 cases per 1 million children younger than 15 years. Approximately 500 cases of Wilms tumor are diagnosed in the United States each year. The incidence is substantially lower in Asians. The male to female ratio in unilateral cases of Wilms tumor is 0.92:1.00, but in bilateral cases it is 0.60:1.00. The mean age at diagnosis is 44 months in unilateral cases of Wilms tumor and 31 months in bilateral cases.[1,2] About 10% of children with Wilms tumor have an associated congenital malformation syndrome.
Syndromes and Other Conditions Associated With Wilms Tumor
Wilms tumor typically develops in otherwise healthy children; however, approximately 10% of children with Wilms tumor have been reported to have a congenital anomaly.[3,4] Of 295 consecutive patients with Wilms tumors seen at the Institute Curie in Paris, 52 (17.6%) had anomalies or syndromes, 43 of which were considered major, and 14 of which were genetically proven tumor predisposition syndromes. Children with Wilms tumors may have associated hemihypertrophy and urinary tract anomalies, including cryptorchidism and hypospadias. Children may have a recognizable phenotypic syndrome (including overgrowth, aniridia, genetic malformations, and others). These syndromes have provided clues to the genetic basis of the disease. The phenotypic syndromes and other conditions have been grouped into overgrowth and nonovergrowth categories. Overgrowth syndromes and conditions are the result of excessive prenatal and postnatal somatic growth.[6,7]
For information about the genes associated with Wilms tumor, including Wilms tumor 1 (WT1) and Wilms tumor 2 (WT2), refer to the Genes Associated With Wilms Tumor section of this summary.
Syndromic causes of Wilms tumor
Nonsyndromic causes of Wilms tumor
Nonsyndromic causes of Wilms tumor include the following:
Two familial Wilms tumor genes have been localized to FWT1 (17q12-q21) and FWT2 (19q13.4).[32,33,34] There are occasional Wilms tumor families with a germline mutation in WT1. In these families, most, but not all, family members have genitourinary tract malformations.[35,36]
Genes Associated With Wilms Tumor
Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of at least ten genes. The changes may be somatic or germline. Several genes, but not all, will be discussed here.
Aberrations in germline or clonal WT1, WT2, and Wnt activation, when combined with stage of development of the nephron, characterize different subsets of Wilms tumor that can be differentiated by using gene expression profiling. This genetic/ontogenic categorization describes some of the heterogeneity among Wilms tumors.
Wilms tumor 1gene (WT1)
The WT1 gene is located on the short arm of chromosome 11 (11p13). The normal function of WT1 is required for normal genitourinary development and is important for differentiation of the renal blastema.
When modern molecular genetic techniques are used in testing, the incidence of germline WT1 mutations is about 11%. Most of these mutations may be diagnosed, or at least highly suspected, on the basis of clinical syndromic findings at or before diagnosis of Wilms tumor. In a United Kingdom Children's Cancer Study Group study of patients entered in clinical trials, about 2% of Wilms tumor patients had germline mutations in WT1 but no genitourinary abnormalities, as detected by WT1 heteroduplex DNA screen followed by sequencing. These were mostly de novo mutations in children presenting before age 2 years, and the tumors were mostly unilateral with stromal histology. The relatively low number of reports of parent and child pairs with Wilms tumors and WT1 mutations may be the result of decreased fertility. However, the offspring of a child who has a parent with Wilms tumor and WT1 mutation will be at risk for developing Wilms tumor.
Germline WT1 mutations in children with Wilms tumors do not confer poor prognoses per se.
Because deletion of WT1 was the first mutation found to be associated with Wilms tumor, WT1 was assumed to be a conventional tumor suppressor gene. However, non-inactivating mutations can result in altered WT1 protein function that also results in Wilms tumor, such as in Denys-Drash syndrome.
WT1 mutations are more common in children with Wilms tumor and one of the following:
WT1deletion and WAGR syndrome
The observation that led to the discovery of WT1 was that children with WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) were at high risk (>30%) for developing Wilms tumor. Germline mutations were then identified at chromosome 11p13 in children with WAGR syndrome. Deletions involved a set of contiguous genes that included WT1 and the PAX6 gene.
Inactivating mutations or deletions in the PAX6 gene lead to aniridia, while deletion of WT1 confers the increased risk of Wilms tumor. Some of the sporadic cases of aniridia are caused by large chromosomal deletions that also include WT1. This results in a 67-fold increased relative risk (95% confidence interval [CI], 8.1–241) of developing Wilms tumor in children with sporadic aniridia. The incidence of Wilms tumor in children with sporadic aniridia is estimated to be about 5%. Seventy-seven percent of aniridia patients with submicroscopic WT1 deletions detectable by high-resolution fluorescence in situ hybridization (FISH) analysis presented with Wilms tumor compared with 42.5% of aniridia patients with visible deletions detected by microscopy. Patients with sporadic aniridia and a normal WT1 gene, however, are not at increased risk of developing Wilms tumor. Children with familial aniridia, generally occurring for many generations, and without renal abnormalities, have a normal WT1 gene and are not at an increased risk of Wilms tumor.[15,46]
Children with WAGR syndrome or other germline WT1 mutations are at increased risk of developing hypertension, nephropathy, and renal failure and are monitored throughout their lives. Patients with Wilms tumor and aniridia without genitourinary abnormalities are at less risk but are monitored for nephropathy or renal failure. Children with Wilms tumor and any genitourinary anomalies are also at increased risk for late renal failure and are monitored. Features associated with germline WT1 mutations that increase the risk of developing renal failure include the following:
Age at tumor diagnosis, frequency of bilaterality, and risk of late-onset renal compromise may vary with the type of mutation.
The mental retardation in WAGR syndrome may be secondary to deletion of other genes, including SLC1A2 or BDNF (brain-derived neurotrophic factor).
WT1 mutations and 11p15 loss of heterozygosity were associated with relapse in patients with very low-risk Wilms tumor in one study of 56 patients who did not receive chemotherapy. These findings await validation but may provide biomarkers by which to stratify patients in the future.
WT1interaction with beta-catenin
Activating mutations of the beta-catenin gene (CTNNB1) have been reported to occur in 15% of Wilms tumor patients. In one study, all but one tumor with a beta-catenin mutation had a WT1 mutation, and at least 50% of the tumors with WT1 mutations had a beta-catenin mutation.[51,52] Activation of beta-catenin in the presence of intact WT1 protein appears to be inadequate to promote tumor development because CTNNB1 mutations are rarely found in the absence of a WT1 or WTX mutation.[53,54] About one-third of Wilms tumors have a somatic mutation in WT1, WTX, and/or CTNNB1.
Wilms tumor 2locus (WT2)
When modern molecular genetic techniques are used in testing, the incidence of germline WT2 aberrations is about 8%. Most of these aberrations may be diagnosed, or at least highly suspected, on the basis of clinical syndromic findings at or before diagnosis of Wilms tumor. However, when 437 children with nonsyndromic Wilms tumor were screened for germline mutations in the WT2 locus, 13 mutations (3% of patients) were found. None of these children had signs of Beckwith-Wiedemann syndrome, although they did have a higher frequency of bilateral tumors and perilobar nephrogenic rests. All were de novo abnormalities, except one novel microdeletion in one child, and their mother was not affected. A similar mutation at the WT2 locus was found in 1 of 22 familial Wilms tumor families tested.
WT2and Beckwith-Wiedemann syndrome
A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5, which, when it is a germline mutation, causes the Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumors have germline epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. Like children with Beckwith-Wiedemann syndrome, these children have an increased incidence of bilateral Wilms tumor or familial Wilms tumor.
Several candidate genes at the WT2 locus comprise the two independent imprinted domains IGF2/H19 and KIP2/LIT1. Loss of heterozygosity, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations. A study of 35 sporadic primary Wilms tumors suggests that more than 80% have somatic loss of heterozygosity or loss of imprinting at 11p15.5. The mechanism resulting in loss of imprinting can be either genetic mutation or epigenetic change of methylation.[49,56] Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5. Interestingly, Wilms tumors in Asian children are not associated with either nephrogenic rests or IGF2 loss of imprinting.
Beckwith-Wiedemann syndrome results from loss of imprinting or heterozygosity of WT2 germline mutations. Observations suggest genetic heterogeneity in the etiology of Beckwith-Wiedemann syndrome, with differing levels of association with risk of tumor formation. Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[15,16,17] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the National Wilms Tumor Study (NWTS).[1,17]
A relationship between epigenotype and phenotype has been shown in Beckwith-Wiedemann syndrome, with a different rate of cancer in Beckwith-Wiedemann syndrome according to the type of alteration of the 11p15 region. The overall tumor risk in Beckwith-Wiedemann syndrome was estimated between 5% and 10%, with a risk between 1% (loss of imprinting at IC2) and 30% (gain of methylation at IC1 and paternal 11p15 isodisomy). Patients with IC1 gain of methylation only developed Wilms tumor, whereas other tumors such as neuroblastoma or hepatoblastoma could occur in patients with paternal 11p15 isodisomy.
Wilms tumor gene on the X chromosome(WTX)
A third gene, WTX, has been identified on the X chromosome and plays a role in normal kidney development. This gene is inactivated in approximately one-third of Wilms tumors, but germline mutations have not been observed in patients with Wilms tumor.WTX mutations are equally distributed between males and females. WTX inactivation is a frequent, but late, event in tumorigenesis and has no apparent effect on clinical presentation or prognosis.
Other genes and chromosomal alterations
Additional genes have been implicated in the pathogenesis and biology of Wilms tumor, including the following:
In an analysis of 212 patients from NWTS-4 and the Pediatric Oncology Group Wilms Biology study, 27% of patients displayed 1q gain. A strong relationship between 1q gain and 1p/16q loss was observed. The 8-year event-free survival (EFS) rate was 76% (95% CI, 63%–85%) for patients with 1q gain and 93% (95% CI, 87%–96%) for those lacking 1q gain (P = .0024). The 8-year overall survival (OS) rate was 89% (95% CI, 78%–94%) for those with 1q gain and 98% (95% CI, 94–99%) for those lacking 1q gain (P = .0075). Gain of 1q was not found to correlate with disease stage. After stratification for stage of disease, 1q gain was associated with a significantly increased risk of disease recurrence (risk ratio estimate, 2.72; P = .0089).
Similar results have been reported by European investigators.
These conflicting results may arise from the greater prognostic significance of 1q gain described above. The loss of heterozygosity of 16q and 1p appear to arise from complex chromosomal events that result in 1q loss of heterozygosity or 1q gain. The change in 1q appears to be the critical tumorigenic genetic event.
The pathology of WT1-associated and DICER1-associated Wilms tumors appears to differ. WT1-associated Wilms tumors are often stromal rich, with rhabdomyomatous differentiation and intralobar nephrogenic rests that are thought to occur early in renal development, while DICER1-associated Wilms tumors are triphasic with abundant blastema and are not associated with nephrogenic rests.
Bilateral Wilms Tumor
Approximately 5% to 10% of individuals with Wilms tumor have bilateral or multicentric tumors. The prevalence of bilateral involvement is higher in individuals with genetic predisposition syndromes than in those without predisposition syndromes; however, 85% of individuals with WAGR or Beckwith-Wiedemann syndrome have unilateral tumors.[18,78]
Only 16% of persons with bilateral Wilms tumor have a WT1 germline mutation, and only 3% of persons with bilateral Wilms tumors have affected family members. Bilateral Wilms tumor with WT1 mutations are associated with early presentation in pediatric patients (age 10 months vs. age 39 months for those without a mutation) and a high frequency of WT1 nonsense mutations in exon 8. The presence of bilateral or multifocal disease implies that a patient has a genetic predisposition for Wilms tumor.
Screening Children Predisposed to Wilms Tumor
Children with a significantly increased predisposition to develop Wilms tumor (e.g., most children with Beckwith-Wiedemann syndrome or other overgrowth syndromes, WAGR syndrome, Denys-Drash syndrome, sporadic aniridia, or isolated hemihypertrophy) are usually screened with ultrasound every 3 months at least until they reach age 8 years.[6,7,15,46] Early-stage, asymptomatic, small Wilms tumors may be discovered and potentially removed with renal-sparing surgery.
Tumor screening programs for each overgrowth syndrome have been suggested, based on published age and incidence of tumor type. Approximately 10% of patients with Beckwith-Wiedemann syndrome will develop a malignancy, with the most common being either Wilms tumor or hepatoblastoma, although adrenal tumors can also occur. Children with hemihypertrophy are also at risk for developing liver and adrenal tumors. Screening with abdominal ultrasound and serum alpha-fetoprotein is suggested until age 4 years. After age 4 years, most hepatoblastomas will have occurred, and imaging may be limited to renal ultrasound, which is quicker and does not require fasting before the exam.
Newborns with sporadic aniridia are usually screened with ultrasound every 3 months until they reach age 8 years, unless genetic testing confirms that they are negative for WT1 deletion.[46,82]
Although the risk for Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown and likely varies with the gene in which the mutation occurred, some experts recommend screening such children with serial ultrasound examinations every 3 months until age 8 years.
The risk of Wilms tumor in children with Klippel-Trénaunay syndrome (a unilateral limb overgrowth syndrome) was no different than the risk in the general population when assessed using the NWTS database. Routine ultrasound surveillance is not recommended.
The frequency of malformations observed in patients with Wilms tumor underlines the need for genetic counseling, molecular and genetic explorations, and follow-up.
A French study  concluded that patients need to be referred for genetic counseling if they have one of the following:
Simple oncological follow-up is indicated when there is no malformation or when there is only one minor malformation.
After genetic counseling takes place, a search for WT1 mutations should be considered for patients who have the following:
A search for an 11p15 abnormality should be considered for patients exhibiting any symptoms of Beckwith-Wiedemann syndrome, hemihypertrophy, or bilateral or familial Wilms tumor.
The following symptoms may be caused by Wilms or other childhood kidney tumors:
Children with Wilms tumors or other renal malignancies may also come to medical attention as a result of the following:
Diagnostic and Staging Evaluation
About 5% of renal masses thought to be Wilms tumor on the basis of clinical and radiological findings are diagnosed as another condition.[87,88] The German Pediatric Oncology study group entered 188 patients on the SIOP-9 trial from 1988 to 1991. However, only 136 patients received preoperative chemotherapy because imaging was regarded as atypical on central review. Nine of the 188 patients (5%) had other diagnoses, including benign tumors and renal cell carcinoma.
Tests and procedures used to evaluate and stage Wilms tumor and other childhood kidney tumors include the following:
Biopsy of a renal mass may be indicated if the mass is atypical for Wilms tumor. Biopsy tissue from inoperable Wilms tumor obtained before chemotherapy may be used for histologic review and initial treatment decisions. The use of biopsy to determine histology in an inoperable tumor remains controversial because biopsy may cause local tumor spread. It is important to recognize that data from NWTS-4 and NWTS-5 have shown conclusively that, because of histologic heterogeneity of Wilms tumor, a significant number of patients have unfavorable histology that is missed during an upfront biopsy but revealed at the time of definitive surgery following chemotherapy.
If the initial imaging studies suggested a possible lesion on the contralateral kidney, the contralateral kidney is formally explored to rule out bilateral involvement. This is done before nephrectomy to exclude bilateral Wilms tumor.
Biopsy is also controversial in patients with bilateral tumors because biopsy rarely detects anaplasia in bilateral Wilms tumor, and the incidence of bilateral tumors being other than Wilms is very low. The current COG study of bilateral Wilms tumor and of patients with unilateral Wilms tumor predisposed to developing bilateral tumors tries to avoid initial biopsy and mandates biopsy after 6 weeks of three-drug chemotherapy.
Children with a renal mass are carefully assessed for signs of associated syndromes such as aniridia, developmental delay, hypospadias, cryptorchidism, pseudohermaphrodism, overgrowth, and hemihypertrophy.
For patients with suspected Wilms tumor, preoperative staging studies include a CT or MRI scan of the abdomen/pelvis and chest to assess intravascular extension or rupture of Wilms tumor.
In North America, local staging of Wilms tumor is performed with CT or MRI of the abdomen and pelvis. Contrast-enhanced CT for Wilms tumor patients has high sensitivity and specificity for detection of cavoatrial tumor thrombus that may impact surgical approach. Routine Doppler evaluation after CT has been performed but is not necessarily required. Large tumor thrombi need to be controlled before surgical approach to the renal mass.
Prognosis and Prognostic Factors
Wilms tumor is a curable disease in most affected children. Since the 1980s, the 5-year survival rate for Wilms tumor with FH has been consistently above 90%. This favorable outcome occurred despite reductions in the length of therapy, dose of radiation, extent of fields irradiated, and the percentage of patients receiving radiation therapy.
The prognosis for patients with Wilms tumor depends on the following:[98,99,100,101]
Adolescents and young adults with Wilms tumor
In an analysis of Wilms tumor patients in the Surveillance, Epidemiology, and End Results (SEER) database, adults (n = 152) had a statistically worse OS (69% vs. 88%, P < .001) than did pediatric patients (n = 2,190), despite previous studies showing comparable outcome with treatment on protocol.[104,105] The inferior outcome of the adult patients on this study may be the result of differences in tumor biology between children and adults, incorrect diagnosis, inadequate staging (e.g., more likely to be staged as localized disease or to not receive lymph node sampling), or undertreatment (e.g., not receiving radiation therapy). Additional factors in this SEER report that may have contributed to a worse OS in adult patients include the size of the study and lack of central review of pathology. Adolescent and young adult patients up to age 30 years are now eligible for treatment on the COG Wilms tumor protocols.
The inferior outcome of older patients is not explained entirely by inadequate treatment or not being treated according to the pediatric Wilms tumor protocol. In a U.K. study looking at the outcome of patients aged 10 to 16 years (N = 50) registered on the U.K. Wilms Tumor 3 and SIOP 2001 Wilms tumor trials, patients in this age group had a higher percentage of diffuse anaplastic tumors. The overall 5-year survival was 63% for patients aged 10 to 16 years (43% for anaplastic tumors), which is significantly lower than the outcome for younger patients with Wilms tumor. However, SEER 5-year relative survival of nephroblastoma between 2003 and 2009 did not show differences among age groups from younger than 1 year to age 10 to 14 years.
Histologic Findings in Wilms Tumor
Although most patients with a histologic diagnosis of Wilms tumor do well with current treatment, approximately 10% of patients have histopathologic features that are associated with a worse prognosis, and in some types, with a high incidence of relapse and death. Wilms tumor can be separated into the following two prognostic groups on the basis of tumor and kidney histopathology:
Favorable histology (FH)
Histologically, Wilms tumor mimics the triphasic development of a normal kidney consisting of blastemal, epithelial (tubules), and stromal cell types. Not all tumors are triphasic, and monophasic patterns may present diagnostic difficulties.
While associations between histologic features and prognosis or responsiveness to therapy have been suggested, with the exception of anaplasia, none of these features have reached statistical significance in North American treatment algorithms, and therefore, do not direct the initial therapy.
Anaplastic histology accounts for about 10% of Wilms tumors. Anaplastic histology is the single most important histologic predictor of response and survival in patients with Wilms tumor. Tumors occurring in older patients (aged 10–16 years) have a higher incidence of anaplastic histology. In bilateral tumors, 12% to 14% have been reported to have anaplastic histology in one kidney.[109,110]
The following two histologic criteria must be present for the diagnosis of anaplasia:
Changes on 17p consistent with mutations in the p53 gene have been associated with foci of anaplastic histology. Focal anaplasia is defined as the presence of one or more sharply localized regions of anaplasia in a primary tumor. All of these factors lend support to the hypothesis that anaplasia evolves as a late event from a subpopulation of Wilms tumor cells that have acquired additional genomic lesions. Focal anaplasia does not confer as poor a prognosis as does diffuse anaplasia.[100,112,113]
Anaplasia correlates best with responsiveness to therapy rather than to tumor aggressiveness. It is most consistently associated with poor prognosis when it is diffusely distributed and when identified at advanced stages. These tumors are more resistant to the chemotherapy traditionally used in children with FH Wilms tumor.
Nephrogenic rests are abnormally retained embryonic kidney precursor cells arranged in clusters. Nephrogenic rests are found in about 1% of unselected pediatric autopsies, 35% of kidneys with unilateral Wilms tumors, and nearly 100% of kidneys with bilateral Wilms tumors.[114,115]
The term nephroblastomatosis is defined as the presence of diffuse or multifocal nephrogenic rests. There are two types: intralobar nephrogenic rests and perilobar nephrogenic rests. Diffuse hyperplastic perilobar nephroblastomatosis is defined as nephroblastomatosis forming a thick rind around one or both kidneys and is considered a preneoplastic condition.
The type and percentage of nephrogenic rests vary in patients with unilateral or bilateral disease. Patients with bilateral Wilms tumor have a higher proportion of perilobar rests (52%) than of intralobar or combined rests (32%) and higher relative proportions of rests, compared with patients with unilateral tumors (18% perilobar and 20% intralobar or both).
Patients with any type of nephrogenic rest in a kidney removed for nephroblastoma are considered at increased risk for tumor formation in the remaining kidney. This risk decreases with patient age.
Extrarenal nephrogenic rests are rare and may develop into extrarenal Wilms tumor.
Stage Information for Wilms Tumor
Both the results of the imaging studies and the surgical and pathologic findings at nephrectomy are used to determine the stage of disease. The stage is the same for tumors with FH or anaplastic histology. Thus, the stage information is characterized by a statement of both criteria (for example, stage II, FH or stage II, anaplastic histology).[108,117]
The staging system was originally developed by the NWTS Group and is still used by the COG. The staging system and incidence by stage are outlined below.
In stage I Wilms tumor (43% of patients), all of the following criteria must be met:
For a tumor to qualify for certain therapeutic protocols such as very low-risk stage I, regional lymph nodes must be examined microscopically. Lymph node sampling is recommended for all patients.
In stage II Wilms tumor (20% of patients), the tumor is completely resected, and there is no evidence of tumor at or beyond the margins of resection. The tumor extends beyond the kidney as evidenced by any one of the following criteria:
Rupture or spillage confined to the flank, including biopsy of the tumor, is now included in stage III by the COG Renal Tumor Committee; however, data to support this approach are controversial.
In stage III Wilms tumor (21% of patients), there is postsurgical residual nonhematogenous tumor that is confined to the abdomen. Any one of the following may occur:
Lymph node involvement and microscopic residual disease are highly predictive of outcome in patients with stage III FH Wilms tumor.
In stage IV Wilms tumor (11% of patients), hematogenous metastases (lung, liver, bone, brain) or lymph node metastases outside the abdominopelvic region are present. The presence of tumor within the adrenal gland is not interpreted as metastasis and staging depends on all other staging parameters present. According to the criteria described above, the primary tumor is assigned a local stage, which determines local therapy. For example, a patient may have stage IV, local stage III disease.
In stage V Wilms tumor (5% of patients), bilateral involvement by tumor is present at diagnosis. A previous attempt was made to stage each side according to the above criteria on the basis of the extent of disease. The ongoing COG-AREN0534 protocol is testing the approach of preoperative chemotherapy without local biopsy in hopes of reducing tumor size to allow renal-sparing surgical procedures. In these patients, renal failure rates approach 15% at 15 years posttreatment, making renal-sparing treatment important.
Treatment for Wilms Tumor
Because of the relative rarity of Wilms tumor, all patients with this tumor should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon and/or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) who have experience treating Wilms tumor is necessary to determine and implement optimal treatment.
Most randomized clinical studies for treatment of children with Wilms tumor have been conducted by two large clinical groups. There are differences between the two groups that affect staging and classification.
This summary focuses on the NWTS (now COG Renal Tumor Committee) results and studies.
The major treatment and study conclusions of NWTS-1 through NWTS-5 are as follows:
The following operative principles have also evolved from NWTS trials:
Renal-sparing surgery remains controversial and is not recommended, except for children with the following:; [Level of evidence: 3iiB]
The use of renal-sparing surgery for bilateral tumors is under investigation.
In North America, renal-sparing surgery (partial nephrectomy) of unilateral Wilms tumor following administration of chemotherapy to shrink the tumor mass is considered investigational.[132,133]
Hilar and periaortic lymph node sampling is appropriate even if the nodes appear normal.[127,134] Furthermore, any suspicious node basin is sampled. Margins of resection, residual tumor, and any suspicious node basins are marked with titanium clips.
Wilms tumor rarely invades adjacent organs; therefore, resection of contiguous organs is rarely indicated. There is an increased incidence of complications occurring in more extensive resections that involve removal of additional organs beyond the diaphragm and adrenal gland. This has led to the recommendation in current COG protocols that these patients should be considered for initial biopsy, neoadjuvant chemotherapy, and then secondary resection. Primary resection of liver metastasis is not recommended.
Preoperative chemotherapy before nephrectomy is indicated in the following situations:[127,135,137,138,139,140]
Preoperative chemotherapy follows a biopsy unless the patient is being treated on COG-AREN0534. The biopsy may be performed through a flank approach.[141,142,143,144,145,146] Preoperative chemotherapy includes doxorubicin in addition to vincristine and dactinomycin unless anaplastic histology is present; in such cases, then chemotherapy includes treatment with regimen I (refer to Table 2 below). The chemotherapy generally makes tumor removal easier by decreasing the size and vascular supply of the tumor; it may also reduce the frequency of surgical complications.[91,135,137,146,147]
Newborns and all infants younger than 12 months who will be treated with chemotherapy require a 50% reduction in chemotherapy dose compared with the dose given to older children. This reduction diminishes the toxic effects reported in children in this age group enrolled in NWTS studies while maintaining an excellent overall outcome.
Liver function tests in children with Wilms tumor are monitored closely during the early course of therapy because hepatic toxic effects (sinusoidal obstructive syndrome, previously called veno-occlusive disease) have been reported in these patients.[150,151] Dactinomycin or doxorubicin should not be administered during radiation therapy. Patients who develop renal failure while undergoing therapy can continue receiving chemotherapy with vincristine, dactinomycin, and doxorubicin. Vincristine and doxorubicin can be given at full doses; however, dactinomycin is associated with severe neutropenia. Reductions in dosing these agents may not be necessary, but accurate pharmacologic and pharmacokinetic studies are needed while the patient is receiving therapy.[152,153]
Postoperative radiation therapy to the tumor bed is required when a biopsy is performed or in the setting of local tumor stage III.
Table 2 describes the standard chemotherapy regimens used to treat Wilms tumor.
Standard treatment options for stage I Wilms tumor
Table 3 provides an overview of the standard treatment and survival data for stage I Wilms tumor, based on published results.
The COG addressed the question of whether a subset of stage I Wilms tumor patients could be treated with surgery alone. The NWTS-5 (COG-Q9401) trial investigated this approach for children younger than 2 years at diagnosis with stage I FH Wilms tumors that weigh less than 550 g.
Evidence (surgery only for children younger than 24 months at diagnosis with stage I FH tumor that weighed <550 g):
Standard treatment options for stage II Wilms tumor
Table 4 provides an overview of the standard treatment and survival data for stage II Wilms tumor, based on published results.
On NWTS-3 through NWTS-5, patients with intraoperative spill were divided into two groups: (1) those with diffuse spillage involving the whole abdominal cavity; and (2) those with local spillage confined to the flank. Patients with diffuse spillage were treated with radiation therapy to the entire abdomen and three-drug chemotherapy (vincristine, dactinomycin, and doxorubicin), whereas patients with local spillage were treated with vincristine and dactinomycin only. On the basis of an analysis of patients treated on NWTS-3 and NWTS-4 indicating that patients with stage II disease and local spillage had inferior OS compared with patients with stage II disease without local spillage, ongoing COG studies treat patients with local spillage with doxorubicin and flank radiation. This approach is controversial and has not been tested; therefore, it should not be considered standard.
In a review of 499 patients from NWTS-4 with stage II, FH Wilms tumor, 95 of the patients experienced tumor spill. The 8-year RFS and OS for patients who experienced tumor spill and were treated with vincristine and dactinomycin without flank radiation therapy was lower, at 75.7% and 90.3%, than the 85% and 95.6% rates for those who did not experience tumor spill. None of these differences achieved statistical significance.
Standard treatment options for stage III Wilms tumor
Table 5 provides an overview of the standard treatment and survival data for stage III Wilms tumor, based on published results.
The outcome of patients with peritoneal implants treated with gross resection, three-drug chemotherapy, and total-abdominal radiation (10.5 Gy) is similar to that of other stage III patients.[Level of evidence: 2A]
For patients classified as stage III purely on the basis of local spill, refer to the Standard treatment options for stage II Wilms tumor section of this summary.
Standard treatment options for stage IV Wilms tumor
Table 6 provides an overview of the standard treatment and survival data for stage IV Wilms tumor, based on published results.
Stage IV disease is defined by the presence of hematogenous metastases to the lung, liver, bone, brain, or other sites, with the lung being the most common site. Historically, chest X-rays were used to detect pulmonary metastases. The introduction of CT created controversy because many patients had lung nodules detected by chest CT scans that were not seen on chest X-rays. Management of newly diagnosed patients with FH Wilms tumor who have lung nodules detected only by CT scans (with negative chest X-ray) has elicited controversy as to whether they need to be treated with additional intensive treatment that is accompanied by acute and late toxicities.
Evidence (treatment of pulmonary nodules detected by chest CT scan only):
The issue of whether radiation can be omitted in patients with FH Wilms tumor and pulmonary metastases (identified by chest CT scans) has been studied prospectively in North America in the COG-AREN0533 trial. COG-AREN0533 patients underwent 6 weeks of chemotherapy consisting of vincristine, dactinomycin, and doxorubicin and were reevaluated to assess the response of their pulmonary metastases. Patients whose pulmonary metastases had completely resolved were spared pulmonary irradiation and continued with the same chemotherapy. If the pulmonary metastases were still present at that time, patients were treated with chemotherapy in which cyclophosphamide and etoposide were added, and they also underwent pulmonary irradiation. The trial is closed, and results are pending.
Retrospective studies from Europe have examined the impact of omitting pulmonary radiation in patients with pulmonary metastases diagnosed by chest X-ray. European investigators omitted radiation from the treatment of most patients with Wilms tumor and pulmonary metastases as identified on chest X-ray who were treated on the SIOP-93-01 trial. The European approach to renal tumors differs from the approach used in North America. All patients who were shown to have a renal tumor by imaging underwent 9 weeks of prenephrectomy chemotherapy consisting of vincristine, dactinomycin, and doxorubicin.
Evidence (treatment of pulmonary nodules detected by chest X-ray):
It is important to note that patients in Europe receive higher cumulative doses of dactinomycin and doxorubicin before their pulmonary metastases are reevaluated than do patients in North America. The European experience cannot be directly applied to North America, although it suggests that for patients with nonanaplastic histology who are in a complete remission with chemotherapy, radiation may be omitted without impacting outcome.
The presence of liver metastases at diagnosis is not an independent adverse prognostic factor in patients with stage IV Wilms tumor.
Treatment options for stage V and those predisposed to developing bilateral Wilms tumor
Currently, there is not a standard approach for the treatment of stage V Wilms tumor (bilateral Wilms tumor at diagnosis) and those predisposed to developing Wilms tumor.
Management of a child with bilateral Wilms tumor is very challenging. The goals of therapy are to eradicate all tumor and to preserve as much normal renal tissue as possible, with the hope of decreasing the risk of chronic renal failure among these children.
In the NWTS-4 trial, bilateral Wilms tumor patients had a lower EFS and OS than did patients with localized Wilms tumor (including anaplastic histology), except for stage IV disease, in which OS was higher for patients with bilateral Wilms. The NWTS-4 study reported that the 8-year EFS for patients with bilateral FH Wilms tumor was 74% and the OS was 89%; for patients with anaplastic histology, the EFS was 40% and the OS was 45%. The NWTS-5 (COG-Q9401) study reported the 4-year EFS for bilateral Wilms tumor patients was 61% and the OS was 81%; for patients with anaplastic histology, the EFS was 44% and the OS was 55%.[100,159] Similar outcomes for patients with bilateral Wilms tumor have been reported in Europe.[109,109,160] In a single-institution experience in the Netherlands (N = 41), there was significant morbidity in terms of renal failure (32%) and secondary tumors (20%). The incidence of end-stage renal failure in the Dutch study may be a reflection of a longer follow-up period.
Therapy for stage V Wilms tumor is being studied by the COG. Traditionally, patients have undergone bilateral renal biopsies, with staging of each kidney followed by preoperative chemotherapy. Currently on COG trials, pretreatment biopsies are not required if results of imaging tests are consistent with Wilms tumor. In the past the surgical approach varied according to the size of the tumor, with small tumors being resected and larger tumors being biopsied followed by prenephrectomy chemotherapy. The COG-AREN0534 trial is expected to provide data on whether using vincristine, dactinomycin, and doxorubicin initially is appropriate; in previous studies, approximately 40% of stage V patients did not require anthracyclines.
Preoperative chemotherapy and resection
In the first COG trial to formally study bilateral Wilms tumors (COG-AREN0534), the treatment approach consists of preoperative chemotherapy with vincristine, dactinomycin, and doxorubicin to attempt to shrink the tumor and spare renal parenchyma. As part of this trial, an initial biopsy, laparotomy, or primary tumor excision is not recommended.
Evidence (preoperative chemotherapy):
For patients who are treated with preoperative chemotherapy, the tumor pathology needs to be evaluated after 4 to 8 weeks. For patients not treated on a clinical trial, the ideal time to perform a biopsy or resection is unknown because minimal shrinkage may reflect chemotherapy-induced differentiation or anaplastic histology. A planned attempt at resection or biopsy of apparently unresectable tumor is undertaken no later than 12 weeks from diagnosis. Continuing therapy without evaluating tumor pathology in a patient with bilateral Wilms tumor may miss anaplastic histology or chemotherapy-induced differentiation (including rhabdomyomatous differentiation) and thus increase toxicity for the patient without providing additional benefit for tumor control. Anaplastic histology occurs in 10% of patients with bilateral Wilms tumor, and these tumors respond poorly to chemotherapy.
Once the diagnosis is confirmed, a complete resection is performed. Histologic confirmation of the diagnosis is not straightforward. In a series of 27 patients from NWTS-4, discordant pathology was seen in 20 cases, which highlights the need to obtain tissue from both kidneys. Seven children who were later diagnosed with diffuse anaplastic tumors had core biopsies performed to establish the diagnosis; however, anaplasia was not found. Anaplasia was identified in only three of the nine patients when an open-wedge biopsy was performed and in seven of nine patients who had a partial or complete nephrectomy.
The decision to administer chemotherapy and/or radiation therapy following biopsy or second-look operation is dependent on the tumor's response to initial therapy. More aggressive therapy is required for patients with inadequate response to initial therapy observed at the second procedure or in the setting of anaplasia.[117,159,163,164,165,166,167]
Renal transplantation for children with stage V Wilms tumor is usually delayed until 1 to 2 years have passed without evidence of malignancy. Similarly, renal transplantation for children with Denys-Drash syndrome and Wilms tumor, all of whom require bilateral nephrectomy, is generally delayed 1 to 2 years after completion of initial treatment.
Treatment options under clinical evaluation
Stage V and those predisposed to developing bilateral Wilms tumor
The following treatment option is currently under investigation in COG clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Patients with multicentric tumors, patients with high-risk bilateral tumors, and patients with diffuse hyperplastic nephrogenic rests are being treated on the following protocol:
Upfront intensification with three drugs (vincristine, doxorubicin, and dactinomycin) will be used in large part to move patients to definitive surgery earlier. Repeat imaging will be mandated at 6 weeks. On the basis of patient response to treatment, surgery, definitive surgery, biopsy, or continued chemotherapy will be performed. If biopsy or surgery is performed, chemotherapy or radiation therapy will be given on the basis of histology. Patients undergoing biopsy or continued chemotherapy will have repeat imaging performed at 12 weeks, with definitive surgery performed if results of imaging studies are at all positive.
This approach will identify patients with anaplasia, rhabdomyomatous differentiation, complete necrosis, or stromal differentiation; select them for early surgery; and define the intensity of chemotherapy to be administered.[162,164,170] The decision to administer chemotherapy and/or radiation therapy following the second-look operation is dependent on the response to initial therapy, with more aggressive therapy required for patients with inadequate response to initial therapy observed at the second procedure.[117,163,164,165,166,167]
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I Wilms tumor, stage II Wilms tumor, stage III Wilms tumor, stage IV Wilms tumor and stage V Wilms tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Follow-up after treatment
For patients who have completed therapy for Wilms tumor and exhibit features consistent with genetic predisposition, such as bilateral Wilms tumor, screening involves renal ultrasound examination every 3 months for metachronous tumors during the risk period for that particular syndrome (5 years for WT1-related syndromes; 8 years for Beckwith-Wiedemann syndrome).
Late effects following Wilms tumor therapy
Children treated for Wilms tumor are at increased risk of developing the following:
The cumulative incidence of end-stage renal disease due to chronic renal failure at 20 years from diagnosis of Wilms tumor is low at 3.1% for patients with bilateral Wilms tumor and less than 1% for those with unilateral Wilms tumor. Efforts, therefore, have been aimed toward reducing the intensity of therapy when possible.
(Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)
Incidence of RCC
Malignant epithelial tumors arising in the kidneys of children account for more than 5% of new pediatric renal tumors; therefore, they are more common than clear cell sarcoma of the kidney or rhabdoid tumors of the kidney. Renal cell carcinoma (RCC), the most common primary malignancy of the kidney in adults, is rare in children younger than 15 years. In the older age group of adolescents (aged 15–19 years), approximately two-thirds of renal malignancies are RCC. The annual incidence rate is approximately 4 cases per 1 million children, compared with an incidence of Wilms tumor of the kidney that is at least 29-fold higher.
Conditions Associated With RCC
Conditions associated with RCC include the following:
Screening for the VHL gene is available. To detect clear cell renal carcinoma in these individuals when the lesions are smaller than 3 cm and renal-sparing surgery can be performed, annual screening with abdominal ultrasound or magnetic resonance imaging (MRI) is recommended, beginning at age 8 to 11 years.
(Refer to the Von Hippel-Lindau Syndrome section of the PDQ summary on Genetics of Kidney Cancer (Renal Cell Cancer) for more information.)
Succinate dehydrogenase (SDHB, SDHC, and SDHD) is a Krebs cycle enzyme gene that has been associated with the development of familial RCC occurring with pheochromocytoma/paraganglioma. Germline mutations in a subunit of the gene have been reported in individuals with renal cancer and no history of pheochromocytoma.[8,9]
Genetic Testing for Children and Adolescents With RCC
Indications for germline genetic testing of children and adolescents with RCC to check for a related syndrome are described in Table 7.
Xp11 Translocations Associated With RCC
Translocation-positive carcinomas of the kidney are recognized as a distinct form of RCC and may be the most common form of RCC in children. They are characterized by translocations involving the transcription factor E3 gene (TFE3) located on Xp11.2. The TFE3 gene may partner with one of the following genes:
Another less-common translocation subtype, t(6;11)(p21;q12), involving a fusion Alpha/TFEB, induces overexpression of transcription factor EB (TFEB). The translocations involving TFE3 and TFEB induce overexpression of these proteins, which can be identified by immunohistochemistry.
Previous exposure to chemotherapy is the only known risk factor for the development of Xp11 translocation RCCs. The postchemotherapy interval ranged from 4 to 13 years. All reported patients received either a DNA topoisomerase II inhibitor and/or an alkylating agent.[25,26]
Controversy exists as to the biological behavior of the translocation RCC in children and young adults. Whereas some series have suggested a good prognosis when RCC is treated with surgery alone despite presenting at a higher stage (III/IV) than TFE-RCC, a meta-analysis reported that these patients have poorer outcomes.[27,28,29] The outcomes for these patients are being studied in the ongoing COG-AREN03B2 (NCT00898365) Biology and Classification Study. VEGFR-targeted therapies and mTOR inhibitors seem to be active in Xp11 translocation metastatic RCC. Recurrences have been reported 20 to 30 years after the initial resection of the translocation-associated RCC.
Histology of RCC
Pediatric RCC differs histologically from the adult counterparts. Although the two main morphological subgroups of papillary and clear cell can be identified, about 25% of RCCs show heterogeneous features that do not fit into either of these categories. Childhood RCCs are more frequently of the papillary subtype (20%–50% of pediatric RCCs) and can sometimes occur in the setting of Wilms tumor, metanephric adenoma, and metanephric adenofibroma.
RCC in children and young adults has a different genetic and morphologic spectrum than that seen in older adults.[2,26,31,32]
Prognosis and Prognostic Factors for RCC
The primary prognostic factor for RCC is stage of disease. In a series of 41 children with RCC, the median age was 10 years, with 46% presenting with localized stage I and stage II disease, 29% with stage III disease, and 22% with stage IV disease, according to the Robson classification system. The sites of metastases were the lungs, liver, and lymph nodes. Event-free survival (EFS) and overall survival (OS) were each about 55% at 20 years posttreatment. Patients with stage I and stage II disease had an 89% OS rate, while those with stage III and stage IV disease had a 23% OS rate at 20 years posttreatment.
An important difference between the outcomes in children and adults with RCC is the prognostic significance of local lymph node involvement. Adults presenting with RCC and involved lymph nodes have a 5-year OS of approximately 20%, but the literature suggests that 72% of children with RCC and local lymph node involvement at diagnosis (without distant metastases) survive their disease. In another series of 49 patients from a population-based cancer registry, the findings were similar. In this series, 33% of the patients had papillary subtype, 22% had translocation type, 16% were unclassified, and 6% had clear-cell subtype. Survival at 5 years was 96% for patients with localized disease, 75% for patients with positive regional lymph nodes, and 33% for patients with distant metastatic RCC.
Clinical Features and Diagnostic Evaluation
RCC may present with the following:
Refer to the Wilms tumor Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors. (Refer to the Stage Information for Renal Cell Cancer section of the Renal Cell Cancer Treatment summary for more information about the staging evaluation.)
Standard Treatment Options for RCC
Survival of patients with RCC is affected by stage of disease at presentation and the completeness of resection at radical nephrectomy. OS rates for all patients with RCC range from 64% to 87%. The 5-year survival rates for pediatric RCC is 90% or higher for stage I, higher than 80% for stage II, 70% for stage III, and lower than 15% for stage IV. Retrospective analyses and the small number of patients involved place limitations on the level of evidence in the area of treatment.
Standard treatment options for RCC include the following:
Radical nephrectomy with lymph node dissection
The primary treatment for RCC includes total surgical removal of the kidney and associated lymph nodes.
Renal-sparing surgery with lymph node dissection
Renal-sparing surgery may be considered for carefully selected patients with low-volume localized disease. In two small series, patients who had partial nephrectomies seemed to have outcomes equivalent to those who had radical nephrectomies.[26,36]
As with adult RCC, there is no standard treatment for unresectable metastatic disease in children. The response to radiation is poor, and chemotherapy is not effective. Immunotherapy with such agents as interferon-alpha and interleukin-2 may have some effect on cancer control. Rare spontaneous regression of pulmonary metastasis may occur with resection of the primary tumor.
Several targeted therapies (e.g., sorafenib, sunitinib, bevacizumab, temsirolimus, pazopanib, and everolimus) have been approved for use in adults with RCC; however, these agents have not been tested in pediatric patients with RCC. Case reports of pediatric and adolescent patients with a TFE3 RCC suggest responsiveness to multiple tyrosine kinase inhibitors.[38,39] (Refer to the PDQ summary on adult Renal Cell Cancer Treatment for more information on the use of targeted therapies.)
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood renal cell carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General Information About Rhabdoid Tumors of the Kidney
Rhabdoid tumors are extremely aggressive malignancies that generally occur in infants and young children. The most common locations are the kidney (termed malignant rhabdoid tumor s or MRT) and central nervous system (CNS) (atypical teratoid/rhabdoid tumor), although rhabdoid tumors can also arise in most soft tissue sites. (Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for information on the treatment of central nervous system disease.) Relapses occur early (median time from diagnosis is 8 months).[1,2]
A distinct clinical presentation that suggests a diagnosis of rhabdoid tumor of the kidney includes the following:
(Refer to the Wilms tumor Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)
Approximately two-thirds of patients will present with advanced-stage disease. Bilateral cases have been reported. Rhabdoid tumors of the kidney tend to metastasize to the lungs and the brain. As many as 10% to 15% of patients with rhabdoid tumors of the kidney also have CNS lesions. The staging system used for rhabdoid tumor of the kidney is the same system used for Wilms tumor. (Refer to the Stage Information for Wilms Tumor section of this summary for more information.)
Histologically, the most distinctive features of rhabdoid tumors of the kidney are rather large cells with large vesicular nuclei, a prominent single nucleolus, and in some cells, the presence of globular eosinophilic cytoplasmic inclusions.
Genes Associated With Rhabdoid Tumors of the Kidney
Rhabdoid tumors in all anatomical locations have a common genetic abnormality—loss of function of the SMARCB1/INI1/SNF5/BAF47 gene located at chromosome 22q11.2. SMARCB1 encodes a component of the SWI/SNF (SWItch/Sucrose NonFermentable) chromatin remodeling complex that has an important role in controlling gene transcription.[5,6] Based on gene expression analysis in rhabdoid tumors, it is hypothesized that rhabdoid tumors arise in early progenitor cells during a critical developmental window in which loss of SMARCB1 directly results in repression of neural development, loss of cyclin-dependent kinase inhibition, and trithorax/polycomb dysregulation. Identical mutations may give rise to a brain or kidney tumor.
Germline mutations of SMARCB1 have been documented for patients with one or more primary tumors of the brain and/or kidney, consistent with a genetic predisposition to the development of rhabdoid tumors.[8,9] Approximately 35% of patients with rhabdoid tumors have germline SMARCB1 alterations. In most cases, the mutations are de novo and not inherited from a parent. The median age of children with rhabdoid tumors and a germline mutation or deletion is younger (5 months) than that of children with apparently sporadic disease (18 months). Germline mosaicism has been suggested for several families with multiple affected siblings. It appears that those patients with germline mutations may have the worst prognosis.
Rhabdoid Predisposition Syndrome
Early-onset, multifocal disease and familial cases strongly support the possibility of a rhabdoid predisposition syndrome. This has been confirmed by the presence of germline mutations of SMARCB1 in rare familial cases and in a subset of patients with apparently sporadic rhabdoid tumors. These cases have been labeled as rhabdoid tumor predisposition syndrome, type 1. Thirty-five patients (N = 100) with rhabdoid tumors of the brain, kidney, or soft tissues were found to have a germline SMARCB1 abnormality. These abnormalities included point and frameshift mutations, intragenic deletions and duplications, and larger deletions. Nine cases demonstrated parent-to-child transmission of a mutated copy of SMARCB1. In eight of the nine cases, one or more family members were also diagnosed with rhabdoid tumor or schwannoma; and two of the eight families presented with multiple affected children, consistent with gonadal mosaicism.
Two cases of inactivating mutations in the SMARCA4 gene have been found in three children from two unrelated families, establishing the phenotypically similar syndrome now known as rhabdoid tumor predisposition syndrome, type 2.[11,12] In these cases, SMARCA4 behaves as a classical tumor suppressor, with one deleterious mutation inherited in the germline and the other acquired in the tumor. Another report describes an autosomal dominant pattern of inheritance discovered through an exome sequencing project.
Genetic Testing and Surveillance
Germline analysis is suggested for individuals of all ages with rhabdoid tumors. Genetic counseling is also part of the treatment plan, given the low-but-actual risk of familial recurrence. In cases of mutations, parental screening should be considered, although such screening carries a low probability of positivity. Prenatal diagnosis can be performed in situations where a specific SMARCB1 mutation or deletion has been documented in the family.
Recommendations for surveillance in patients with germline SMARCB1 mutations have been developed on the basis of epidemiology and clinical course of rhabdoid tumors. These recommendations were developed by a group of pediatric cancer genetic experts (including oncologists, radiologists, and geneticists). They have not been formally studied to confirm the benefit of monitoring patients with germline SMARCB1 mutations. The aggressive natural history of the disease, apparently high penetrance, and well-defined age of onset for CNS atypical teratoid/rhabdoid tumor suggest that surveillance could prove beneficial. Given the potential survival benefit of surgically resectable disease, it is postulated that early detection might improve overall survival (OS).
Standard Treatment Options for Rhabdoid Tumor of the Kidney
Because of the relative rarity of this tumor, all patients with rhabdoid tumor of the kidney should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) with experience treating renal tumors is required to determine and implement optimum treatment.
Patients with rhabdoid tumors of the kidney continue to have a poor prognosis. In a review of 142 patients from the National Wilms Tumor Studies (NWTS) NWTS-1 through NWTS-5, age and stage are important prognostic factors:
There is no standard treatment option for rhabdoid tumor of the kidney. The Société Internationale d'Oncologie Pédiatrique (SIOP) renal tumor group has noted that preoperative chemotherapy does not seem to translate into improved survival. Delays in surgery lead to worse survival, compared with patients treated according to direct surgery strategies.
The NWTS-5 (COG-Q9401) trial closed the arm for rhabdoid tumor treatment with cyclophosphamide, etoposide, and carboplatin because poor outcome was observed. Combinations of etoposide and cisplatin; etoposide and ifosfamide; and ifosfamide, carboplatin, and etoposide (ICE chemotherapy) have been used (COG-Q9401).[16,17]
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with rhabdoid tumor of the kidney. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General Information About Clear Cell Sarcoma of the Kidney
Clear cell sarcoma of the kidney is not a Wilms tumor variant, but it is an important primary renal tumor associated with a higher rate of relapse and death than favorable-histology (FH) Wilms tumor. The classic pattern of clear cell sarcoma of the kidney is defined by nests or cords of cells separated by regularly spaced fibrovascular septa. In addition to pulmonary metastases, clear cell sarcoma also spreads to bone, brain, and soft tissue. (Refer to the Wilms tumor Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)
While little is known about the biology of clear cell sarcoma of the kidney, the t(10;17)(q22;p13) translocation has been reported. As a result of the translocation, the YWHAE-FAM22 fusion transcript is formed; this transcript was detected in 12% of cases of clear cell sarcoma of the kidney in one series. 17p13 is the site of the P53 gene; however, this gene does not show abnormal expression and most likely is not involved. Gene expression studies revealed the upregulation of neural markers, with ensuing activation of the sonic hedgehog and Akt pathways. When DNA methylation profiling was used, the epigenetic characteristics of clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, and Ewing sarcoma of the kidney, in comparison with those of the non-neoplastic kidney, exhibited distinct DNA methylation profiles in a tumor type–specific manner. The DNA methylation pattern of the THBS1 CpG site is sufficient for distinction of clear cell sarcoma of the kidney from other pediatric renal tumors.
Younger age and stage IV disease have been identified as adverse prognostic factors for event-free survival (EFS).
Historically, relapses have occurred in long intervals after the completion of chemotherapy (up to 10 years); however, with current therapy, relapses after 3 years are uncommon. The brain is a frequent site of recurrent disease, suggesting that it is a sanctuary site for cells that are protected from the intensive chemotherapy that patients currently receive.[5,7,8] An awareness of the clinical signs of recurrent disease in the brain is important during regular follow-up. There are no standard recommendations for the frequency of brain imaging during follow-up.
Standard Treatment Options for Clear Cell Sarcoma of the Kidney
Because of the relative rarity of this tumor, all patients with clear cell sarcoma of the kidney should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) with experience treating renal tumors is required to determine and implement optimum treatment.
The approach for treating clear cell sarcoma of the kidney is different from the approach for treating Wilms tumor because the overall survival (OS) of children with clear cell sarcoma of the kidney remains lower than that for patients with FH Wilms tumor. All patients undergo postoperative radiation to the tumor bed and receive doxorubicin as part of their chemotherapy regimen.
The standard treatment option for clear cell sarcoma of the kidney is the following:
Surgery, chemotherapy, and radiation therapy
Evidence (surgery, chemotherapy, and radiation therapy):
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with clear cell sarcoma of the kidney. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General Information About Congenital Mesoblastic Nephroma
Mesoblastic nephroma comprises about 5% of childhood kidney tumors, and more than 90% of cases appear within the first year of life. It is the most common kidney tumor found in infants younger than 3 months. The median age of diagnosis is 1 to 2 months. Twice as many males as females are diagnosed. The diagnosis should be questioned when applied to individuals older than 2 years.
When patients are diagnosed in the first 7 months of life, the 5-year event-free survival (EFS) rate is 94%, and the overall survival (OS) rate is 96%. In a report from the United Kingdom of 50 children with mesoblastic nephroma studied on clinical trials and 80 cases from the national registry in the same time period, there were no deaths.
Grossly, mesoblastic nephromas appear as solitary, unilateral masses indistinguishable from nephroblastoma. Microscopically, they consist of spindled mesenchymal cells. Mesoblastic nephroma can be divided into the following two major types:
The risk for recurrence in mesoblastic nephroma is closely associated with the presence of a cellular component and with stage.
(Refer to the Wilms tumor Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)
Standard Treatment Options for Congenital Mesoblastic Nephroma
Standard treatment options for congenital mesoblastic nephroma include the following:
Adjuvant chemotherapy has been recommended for patients with stage III cellular subtype who are aged 3 months or older at diagnosis. However, the benefit of adjuvant therapy will remain unproven with such a low incidence of disease. Infants younger than 2 months with incompletely resected, stage III disease may not need chemotherapy.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with congenital mesoblastic nephroma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General Information About Ewing Sarcoma (Neuroepithelial Tumor) of the Kidney
Ewing sarcoma (neuroepithelial tumor) of the kidney is extremely rare and demonstrates a unique proclivity for young adults. It is a highly aggressive neoplasm, more often presenting with large tumors and penetration of the renal capsule, extension into the renal vein, and in 40% of cases, evidence of metastases.[1,2,3]
Primary Ewing sarcoma of the kidney consists of primitive neuroectodermal tumors characterized by CD99 (MIC-2) positivity and the detection of EWS/FLI-1 fusion transcripts. In Ewing sarcoma of the kidney, focal, atypical histologic features have been seen, including clear cell sarcoma, rhabdoid tumor, malignant peripheral nerve sheath tumors, and paraganglioma.[1,4] (Refer to the PDQ summary on Ewing Sarcoma Treatment for more information.)
Standard Treatment Options for Ewing Sarcoma of the Kidney
There is no standard treatment option for Ewing sarcoma of the kidney. However, multimodal treatment (chemotherapy and radiation therapy) and aggressive surgical approach seem to be associated with a better outcome than previously reported. Consideration should also be given to substituting cyclophosphamide for ifosfamide in patients after they have undergone a nephrectomy. [2,3]
Treatment according to Ewing sarcoma/primitive neuroectodermal tumor protocols should be considered.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with peripheral primitive neuroectodermal tumor of the kidney. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Desmoplastic small round cell tumor of the kidney is a rare, small, round blue tumor of the kidney. It is diagnosed by its characteristic EWS-WT1 translocation. (Refer to the Desmoplastic small round cell tumor section in the PDQ summary on Childhood Soft Tissue Sarcoma Treatment for more information about desmoplastic small round cell tumor of the kidney.)
General Information About Cystic Partially Differentiated Nephroblastoma
Cystic partially differentiated nephroblastoma is a rare cystic variant of Wilms tumor (1%), with unique pathologic and clinical characteristics. It is composed entirely of cysts, and their thin septa are the only solid portion of the tumor. The septa contain blastemal cells in any amount with or without embryonal stromal or epithelial cell type. Several pathologic features distinguish this neoplasm from standard Wilms tumor.
Recurrence has been reported following tumor spillage at surgery.[Level of evidence: 3iiiA]
Standard Treatment Options for Cystic Partially Differentiated Nephroblastoma
Standard treatment options for cystic partially differentiated nephroblastoma include the following:
General Information About Multilocular Cystic Nephroma
Multilocular cystic nephromas are benign lesions consisting of cysts lined by renal epithelium. These lesions can occur bilaterally, and a familial pattern has been reported.
Multilocular cystic nephroma has been associated with pleuropulmonary blastomas, so radiographic imaging studies of the chest are monitored in patients with multilocular cystic nephroma. (Refer to the Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)
Standard Treatment Options for Multilocular Cystic Nephroma
The standard treatment for multilocular cystic nephroma is surgery.
General Information About Primary Renal Synovial Sarcoma
Primary renal synovial sarcoma is a subset of embryonal sarcoma of the kidney and is characterized by the t(x;18)(p11;q11) SYT-SSX translocation. It is similar in histology to the monophasic spindle cell synovial sarcoma and is considered an aggressive tumor with adverse patient outcomes in more than 50% of cases (n = 16). Primary renal synovial sarcoma contains cystic structures derived from dilated, trapped renal tubules. Primary renal synovial sarcoma occurs more often in young adults.
Standard Treatment Options for Primary Renal Synovial Sarcoma
The standard treatment for primary renal synovial sarcoma is chemotherapy. Chemotherapy regimens that are different from those traditionally used for Wilms tumor are used.
General Information About Anaplastic Sarcoma of the Kidney
Anaplastic sarcoma of the kidney is a rare renal tumor that has been identified mainly in patients younger than 15 years.
Patients present with a renal mass, with the most common sites of metastases being the lung, liver, and bones. (Refer to the Wilms tumor Clinical Features and Diagnostic and Staging Evaluation sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)
Cytogenetic abnormalities such as rearrangement between 10q21 and 18p11.2 have been reported. These tumors show pathologic features similar to pleuropulmonary blastoma of childhood (refer to the Pleuropulmonary Blastoma section in the PDQ summary on Unusual Cancers of Childhood for more information) and undifferentiated embryonal sarcoma of the liver (refer to the Treatment of Undifferentiated Embryonal Sarcoma of the Liver section in the PDQ summary on Childhood Liver Cancer for more information).
Standard Treatment Options for Anaplastic Sarcoma of the Kidney
There is no standard treatment for anaplastic sarcoma of the kidney. In the past, these tumors have been identified as anaplastic Wilms tumor and treated accordingly.
General Information About Nephroblastomatosis
Some multifocal nephrogenic rests may become hyperplastic, which may produce a thick rind of blastemal or tubular cells that enlarge the kidney. Nephroblastomatosis may be diagnosed radiographically by magnetic resonance imaging, in which the homogeneity of the hypointense rind-like lesion on contrast-enhanced imaging differentiates it from Wilms tumor. Biopsy often cannot discriminate Wilms tumor from these hyperplastic nephrogenic rests. Differentiation may occur after chemotherapy is administered.
Standard Treatment Options for Nephroblastomatosis
Standard treatment options for nephroblastomatosis include the following:
Current treatment includes vincristine and dactinomycin until nearly complete resolution, as determined by imaging.
Even with treatment (vincristine and dactinomycin), about one-half of children diagnosed with nephroblastomatosis will develop Wilms tumor within 36 months. In a series of 52 patients, 3 patients died of recurrent Wilms tumor. In treated children, as many as one-third of Wilms tumors are anaplastic, probably as a result of selection of chemotherapy-resistant tumors, so early detection is critical. Patients are monitored by imaging at a maximum interval of 3 months, for a minimum of 7 years. Given the high incidence of bilaterality and the subsequent Wilms tumors, renal-sparing surgery is indicated.
These patients are eligible for treatment on the COG-AREN0534 trial with vincristine and dactinomycin.
Patients with recurrent rhabdoid tumor of the kidney, clear cell sarcoma of the kidney, neuroepithelial tumor of the kidney, and renal cell carcinoma should be considered for treatment on available phase I and phase II clinical trials.
Prognosis, Prognostic Factors, and Risk Categories for Recurrent Wilms Tumor
Approximately 15% of patients with favorable-histology (FH) Wilms tumor and 50% of patients with anaplastic Wilms tumor experience recurrence. Historically, the salvage rate for patients with recurrent FH Wilms tumor was 25% to 40%. As a result of modern treatment combinations, the outcome after recurrence has improved up to 60%.[2,3]
A number of potential prognostic features influencing outcome postrecurrence have been analyzed, but it is difficult to separate whether these factors are independent of each other. Also, the following prognostic factors appear to be changing over time as therapy for primary and recurrent Wilms tumor evolves:
The National Wilms Tumor Study-5 (NWTS-5) showed that time to recurrence and site of recurrence are no longer prognostically significant.[2,5] However, in a Société Internationale d'Oncologie Pédiatrique (SIOP) study, patients who experienced a pulmonary relapse within 12 months of diagnosis had a poorer prognosis (5-year overall survival [OS], 47%) than did patients who experienced a pulmonary relapse 12 months or more after diagnosis (5-year OS, 75%).
On the basis of these results, the following three risk categories have been identified:
Treatment of Standard-Risk Relapsed Wilms Tumor
In children who had small stage I Wilms tumor and were treated with surgery alone, the EFS was 84%. All but one child who relapsed was salvaged with treatment tailored to the site of recurrence.[8,5]
Successful retreatment can be accomplished for Wilms tumor patients whose initial therapy consisted of immediate nephrectomy followed by chemotherapy with vincristine and dactinomycin and who relapse.
Treatment options for standard-risk relapsed Wilms tumor include the following:
Surgery, radiation therapy, and chemotherapy
Evidence (surgery, radiation therapy, and chemotherapy):
Treatment of High-Risk and Very High-Risk Relapsed Wilms Tumor
Treatment options for high-risk and very high-risk relapsed Wilms tumor include the following:
Chemotherapy, surgery, and/or radiation therapy
Evidence (chemotherapy, surgery, and/or radiation therapy):
Patients with stage II, stage III, and stage IV anaplastic-histology tumors at diagnosis have a very poor prognosis upon recurrence. The combination of ifosfamide, etoposide, and carboplatin has demonstrated activity in this group of patients, but significant hematologic toxic effects have been observed.
High-dose chemotherapy followed by autologous HSCT has been utilized for recurrent high-risk patients.[10,11,12]
The outcome of autologous stem cell rescue in selected patients is favorable; however, patients with gross residual disease going into transplant do not do as well.[10,12,14] No randomized trials of chemotherapy versus transplant have been reported, and case series suffer from selection bias.
Patients in whom such salvage attempts fail should be offered treatment on available phase I or phase II studies.
Treatment of Recurrent Clear Cell Sarcoma of the Kidney
Clear cell sarcoma of the kidney has been characterized by late relapses. However, in NWTS-5, most relapses occurred within 3 years, and the most common site of recurrence was the brain.
The optimal treatment of relapsed clear cell sarcoma of the kidney has not been established. Treatment of patients with recurrent clear cell sarcoma of the kidney depends on initial therapy and site of recurrence.
Treatment options for recurrent clear cell sarcoma of the kidney include the following:
Cyclophosphamide and carboplatin should be considered if not used initially. Patients with recurrent clear cell sarcoma of the kidney involving the brain have responded to treatment with ifosfamide, carboplatin, and etoposide (ICE) coupled with local control consisting of either surgical resection and/or radiation.[Level of evidence: 2A]
The use of high-dose chemotherapy followed by stem cell transplant is undefined in patients with recurrent clear cell sarcoma of the kidney.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent Wilms tumor and other childhood kidney tumors. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
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This summary was comprehensively reviewed and extensively revised.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of Wilms tumor and other childhood kidney tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Wilms Tumor and Other Childhood Kidney Tumors Treatment are:
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Levels of Evidence
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The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Wilms Tumor and Other Childhood Kidney Tumors Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/wilms/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2014-06-27
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Last modified on: 21 November 2014